Abstract
Background: Anxiety disorders are common psychiatric conditions that are highly comorbid with each other and related phenotypes such as depression, likely due to a shared genetic basis. Fear-related behaviors in mice have long been investigated as potential models of anxiety disorders, making integration of information from both murine and human genetic data a powerful strategy for identifying potential susceptibility genes for these conditions. Methods: We combined genome-wide association analysis of fear-related behaviors with strain distribution pattern analysis in heterogeneous stock mice to identify a preliminary list of 52 novel candidate genes. We ranked these according to three complementary sources of prior anxiety-related genetic data: 1) extant linkage and knockout studies in mice, 2) a meta-analysis of human linkage scans, and 3) a preliminary human genome-wide association study. We genotyped tagging single nucleotide polymorphisms covering the nine top-ranked regions in a two-stage association study of 1316 subjects from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders chosen for high or low genetic loading for anxiety-spectrum phenotypes (anxiety disorders, neuroticism, and major depression). Results: Multiple single nucleotide polymorphisms in the PPARGC1A gene demonstrated association in both stages that survived gene-wise correction for multiple testing. Conclusions: Integration of genetic data across human and murine studies suggests PPARGC1A as a potential susceptibility gene for anxiety-related disorders.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 888-896 |
| Number of pages | 9 |
| Journal | Biological Psychiatry |
| Volume | 70 |
| Issue number | 9 |
| DOIs | |
| State | Published - Nov 1 2011 |
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Keywords
- Anxiety disorder
- candidate gene
- data integration
- depression
- genetic association
- internalizing
ASJC Scopus subject areas
- Biological Psychiatry
Cite this
Prioritization and association analysis of murine-derived candidate genes in anxiety-spectrum disorders. / Hettema, John M.; Webb, Bradley T.; Guo, An Yuan; Zhao, Zhongming; Maher, Brion; Chen, Xiangning; An, Seon Sook; Sun, Cuie; Aggen, Steven H.; Kendler, Kenneth S.; Kuo, Po Hsiu; Otowa, Takeshi; Flint, Jonathan; Van Den Oord, Edwin J.
In: Biological Psychiatry, Vol. 70, No. 9, 01.11.2011, p. 888-896.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Prioritization and association analysis of murine-derived candidate genes in anxiety-spectrum disorders
AU - Hettema, John M.
AU - Webb, Bradley T.
AU - Guo, An Yuan
AU - Zhao, Zhongming
AU - Maher, Brion
AU - Chen, Xiangning
AU - An, Seon Sook
AU - Sun, Cuie
AU - Aggen, Steven H.
AU - Kendler, Kenneth S.
AU - Kuo, Po Hsiu
AU - Otowa, Takeshi
AU - Flint, Jonathan
AU - Van Den Oord, Edwin J.
PY - 2011/11/1
Y1 - 2011/11/1
N2 - Background: Anxiety disorders are common psychiatric conditions that are highly comorbid with each other and related phenotypes such as depression, likely due to a shared genetic basis. Fear-related behaviors in mice have long been investigated as potential models of anxiety disorders, making integration of information from both murine and human genetic data a powerful strategy for identifying potential susceptibility genes for these conditions. Methods: We combined genome-wide association analysis of fear-related behaviors with strain distribution pattern analysis in heterogeneous stock mice to identify a preliminary list of 52 novel candidate genes. We ranked these according to three complementary sources of prior anxiety-related genetic data: 1) extant linkage and knockout studies in mice, 2) a meta-analysis of human linkage scans, and 3) a preliminary human genome-wide association study. We genotyped tagging single nucleotide polymorphisms covering the nine top-ranked regions in a two-stage association study of 1316 subjects from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders chosen for high or low genetic loading for anxiety-spectrum phenotypes (anxiety disorders, neuroticism, and major depression). Results: Multiple single nucleotide polymorphisms in the PPARGC1A gene demonstrated association in both stages that survived gene-wise correction for multiple testing. Conclusions: Integration of genetic data across human and murine studies suggests PPARGC1A as a potential susceptibility gene for anxiety-related disorders.
AB - Background: Anxiety disorders are common psychiatric conditions that are highly comorbid with each other and related phenotypes such as depression, likely due to a shared genetic basis. Fear-related behaviors in mice have long been investigated as potential models of anxiety disorders, making integration of information from both murine and human genetic data a powerful strategy for identifying potential susceptibility genes for these conditions. Methods: We combined genome-wide association analysis of fear-related behaviors with strain distribution pattern analysis in heterogeneous stock mice to identify a preliminary list of 52 novel candidate genes. We ranked these according to three complementary sources of prior anxiety-related genetic data: 1) extant linkage and knockout studies in mice, 2) a meta-analysis of human linkage scans, and 3) a preliminary human genome-wide association study. We genotyped tagging single nucleotide polymorphisms covering the nine top-ranked regions in a two-stage association study of 1316 subjects from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders chosen for high or low genetic loading for anxiety-spectrum phenotypes (anxiety disorders, neuroticism, and major depression). Results: Multiple single nucleotide polymorphisms in the PPARGC1A gene demonstrated association in both stages that survived gene-wise correction for multiple testing. Conclusions: Integration of genetic data across human and murine studies suggests PPARGC1A as a potential susceptibility gene for anxiety-related disorders.
KW - Anxiety disorder
KW - candidate gene
KW - data integration
KW - depression
KW - genetic association
KW - internalizing
UR - http://www.scopus.com/inward/record.url?scp=80053932587&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053932587&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2011.07.012
DO - 10.1016/j.biopsych.2011.07.012
M3 - Article
C2 - 21871609
AN - SCOPUS:80053932587
VL - 70
SP - 888
EP - 896
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
IS - 9
ER -